Psoriasis-Like Cutaneous Inflammation in Mice Lacking Interleukin-1 Receptor Antagonist

Abstract

Interleukin-1 receptor antagonist-deficient (Il1rn-/-) BALB/c mice developed inflammation localized to the skin of the ear pinna in 64% of the cases examined. Histopathologically, the disease had many features resembling human psoriasis, suggesting that it might be a useful disease model. The epidermis became thickened and hypertrophic, and expressed the immature keratin, K6, throughout. The stratum corneum showed parakeratotsis. Large epidermal projections formed into a grossly thickened dermis and both tissues were infiltrated by leukocytes. Neutrophil-rich microabscesses formed beneath the stratum corneum. Dendritic cells and activated T cells of both helper classes were identified in both the dermis and epidermis, while a high density of macrophages was seen in the dermis, where mast cells were also prominent. Dense patterns of apparently activated small dermal vessels were seen in the diseased dermis. Cutaneous inflammation, along with arterial inflammation and arthritis, is the third site-specific, inflammatory disease to be found to affect Il1rn-/- BALB/c mice. None of the diseases affected Il1rn-/- C57BL/6. In F2 hybrids of Il1rn-/- BALB/c and C57BL/6, cutaneous inflammation was absent, aortic inflammation was common, and arthritis was rare, indicating that the sets of background modifier genes that cause susceptibility to each disease are not fully overlapping.

TNF, but Not IL-6 and IL-17, Is Crucial for the Development of T Cell-Independent Psoriasis-Like Dermatitis in Il1rn−/− Mice

“…1D). These histological features of the Il1rn 2/2 epidermis resembled those seen in human psoriasis vulgaris, as reported previously (21,22).…”

“…Given that arthritis and aortitis, which develop in the same Il1rn 2/2 animals, result from autoimmune mechanisms that are strictly dependent on T cells, the reason underlying the independence of psoriasiform skin lesion from autoimmunity against skin Ags is not clear; it is possible that keratinocytes are efficient producers of inflammatory cytokines and chemokines upon stimulation with IL-1, such that the action of these inflammatory mediators is sufficient to induce inflammation without the involvement of the immune system. We do not exclude the possibility completely, however, that immune responses function in the elicitation phase, because abundant dendritic cells and activated T cells are detected in psoriasiform lesions of affected Il1rn 2/2 mice (21,22). Consistent with this possibility, we observed development of dermatitis in Il1rn 2/2 BMC-transferred WT mice at the late stage, although the incidence was low (Table IV).…”

“…Previously, we and Nicklin et al (18)(19)(20) demonstrated that Il1rn 2/2 mice develop chronic arthritis (18) and aortic inflammation (19,20). These mice also develop cutaneous inflammation characterized by extensive thickening of the epidermis associated with hyperkeratosis of the skin, closely resembling psoriasis in humans (21)(22)(23). Because elevated levels of auto-Abs were detected in the sera, and adoptive transfer of Il1rn 2/2 CD4 + T cells induced arthritis and aortitis in nude mice, it was suggested that T cell-mediated autoimmunity plays an essential role in the development of these inflammatory diseases in Il1rn 2/2 mice (18,20,24).…”

Toll IL-1R8/Single Ig IL-1–Related Receptor Regulates Psoriasiform Inflammation through Direct Inhibition of Innate IL-17A Expression by γδ T Cells

“…The role of IL-1R1 signaling has received renewed focus in the context of psoriasiform inflammation as a consequence of observations implicating the IL-23/IL-17 axis as a central mediator of disease (19). Interestingly mice deficient in IL-1R1 antagonist, an endogenous suppressor of IL-1R1 signaling, develop spontaneous autoimmune inflammation in the skin (38). This phenotype is strikingly similar to common manifestations of human psoriasis, with marked acantosis, hyperkeratosis, and a nucleated cell infiltrate.…”

The Psoriatic Transcriptome Closely Resembles That Induced by Interleukin-1 in Cultured Keratinocytes

“…We have previously demonstrated that transgenic mice overexpressing IL-1␣ in basal keratinocytes developed focal inflammatory skin lesions, 43 whereas others have reported psoriasiform lesions on BALB/c IL-1 receptor antagonist knockout mice. 44 The strong induction by IL-1␣ of antimicrobial molecules is of particular interest. S100A7 has been shown recently to exhibit potent antimicrobial properties, particularly against E. coli.…”